Search

A new family of analogs of steganacin, an important antimitotic compound, was accessed. It takes advantage of a completely stereoselective sequence of two key steps. The central dihydropyrane core is built by a highly diastereoselective and facially controlled hetero-Diels–Alder reaction. It is followed by a nonphenolic biaryl oxidative coupling with a complete atropo-stereoselectivity. It leads to a quick way to form cyclic biaryl lignans.

(2′ R ,3 S ,4 S ,5 R )-(−)-Homoharringtonine 2 was synthesized by direct esterification of cephalotaxine, using the activatedforms of suitably substituted tetrahydropyrancarboxylic acids as sterically compact chiral side-chain precursors, followed by selective ring opening of the resulting (2′ R ,3 S ,4 S ,5 R )-(−)-anhydrohomoharringtonine 6 . Both enantiomers of the anhydro acyl moiety were prepared either by asymmetric α-hydroxyalkylation of the suitably substituted ethylenic α-ketoester 7 followed by acidic cyclisation, or by resolving the corresponding racemic mixture via formation of diastereomers with (−)-quinine. Racemic cephalotaxine, as well as both its enantiomers, were prepared from natural -partially racemized- (−)-cephalotaxine 1 .

Megacerotonic acid 1 has a highly exceptional structure, since it is probably the only γ-butyrolactone lignan in which the lactone ring is substituted by an aryl, an arylidene and a carboxy group. The structure of this lignan was confirmed by a racemic total synthesis which involved as key-steps a Stobbe condensation of the 3-arylglutaric ester 8 with p -anisaldehyde 9 , and the hydroxylation at C-4 of the intermediate 2,3-disubstituted glutaric ester 14 .

A systematic study of redox couples in fluoro acid medium has been carried out for the oxidative coupling of bisbenzocyclooctadiene lignan precursors. Tl2O3 and Re2O7 were found to be the more efficient reagents with precursors possessing methylenedioxy substituents for the former and only methoxy groups for the latter. Finally, oxidative coupling of a phenolic dibenzylbutane led to a mixture of two BBCOD's, resulting from para and ortho coupling to the phenolic group.

Efficient access to masked β-amino-aldehydes was performed starting from 6-alcoxy tetrahydrooxazinone 6a–d (6-ATO). Transacetalization leads to the opening of the cycle to form either unsymmetric acetal 7 or symmetric acetals 16–18. These amino acetals are key compounds, obtained with 99% ee, which can be engaged in efficient peptide coupling. This method could easily provide peptides aldehydes or small amido aldehydes as exemplified with the formal synthesis of ent-Maraviroc.

The total synthesis of the racemic furano bisbenzocycloheptene 3 is described. The compound 3, which contains five asymmetric centres, is the 5,8-bis-epimer of the tetra- O -methyl derivative of metasequirin-B (1), a norcycloneolignan of unusual structure.

A systematic study of oxidants used in fluoro acid medium allowed us to increase notably the number of efficient reagents for the non-phenolic oxidative coupling of lignan and alkaloid precursors. If dibenzylbutanolide had no methylenedioxyle group, Re 2 O 7 and RuO 2 .2H 2 O were the most efficient. With a methylenedioxyle group, best results were obtained with Tl 2 O 3 , Mn(OAc) 3 .2H 2 O and Ce(OH) 4 . Finally, aporphines were obtained with good yields with Ce(OH) 4 , RuO 2 .2H 2 O and Fe(OH)(OAc) 2 .

(−)-α-Conidendrin 1 was synthesized according to a general reactionscheme that could be applied to other retrolignans as well. Thus, treatment of the optically active β-benzyl-γ-butyrolactone ( R )-(+)- 4 with NBS, followed with benzyl alcohol, selectively introduced a benzyloxy group in the benzylic position and afforded the mixture of epimers 7 . α-Alkylation of the lithium enolate of the corresponding silyl ethers 10 , with O -benzylvanillyl bromide 11 , gave the trans disubstituted lactones 13 (2 epimers). Catalytic hydrogenolysis (Pd-C) of 13 selectively split the aryl benzyl ether linkage, and gave the compounds 14 . Intramolecular Friedel-Crafts cyclization of the latter, using the benzyloxy group as the leaving group, was induced with BF 3 -Et 2 O and afforded (−)-α-conidendrin 1 in 36% overall yield from methyl α-vanillylhemis uccinate ( R )-(+)- 17 .

Resume Racemic and optically active α,β-dibenzyl-γ-butyrolactones (of synthetic origin) were hydroxylated in the α position with respect to the carbonyl group, using oxygen in the presence of LHDS. This led to (−)-trachelogenin 1 , (−)-nortrachelogenin 2 and (+)-wikstromol 3 , whose interesting pharmacological properties were recently described. These natural lignans were correlated to (±)-methyltrachelogenin 12 whose relative structure was definitely established by X-ray cristallography.

Resolution of methyl α-(3,4,5-trimethoxybenzyl) hemisuccinate, (R,S)-2, by means of (−)-ephedrine, followed by Ca(BH 4 ) 2 reduction, afforded (R)−(+)-β-(3,4,5-trimethoxybenzyl) butanolide. This lactone was used as a starting material for the asymmetric syntheses of eight recently discovered lignans belonging to, or deriving from, the α,β-dibenzylbutanolide series, such as cubebinone and dihydroclusin

Under Lewis acid conditions, reaction of N -Boc, O -Me acetals with the ( R )-(+)- O -vinyl-pantolactone does not lead to the expected dihydrooxazine, but to the corresponding tetrahydrooxazinone, as a result of the loss of the t -Bu group. A diastereoselective and asymmetrical way to these new heterocyclic compounds is described, together with the first evidence of their ability to undergo N -acylation.

The biphenyl 16 (obtained from α-bromopiperonal and the aromatic iodide 14 by a modified Ullmann reaction) was cyclized by intramolecular hydroxyalkylation to the isomeric alcohols 17a and 17b . These were oxidized using Jones' reagent, to afford the enol 18a , together with the tautomeric β-ketolactone Decarboxylation of this mixture using barium hydroxide, followed by Jones' oxidation gave the isomeric γ-ketoacids 11a and 11b . These were converted to (±)-steganone 1 using Raphael's method, in an overall yield of ca 10% starting from 3, 4, 5-trimethoxybenzaldehyde, and in 20,7% yield, starting from the biphenyl 16 .

Michael addition of the carbanion of the dithian 8 on butenolide, followed by alkylation with the benzylic bromide 11 and regeneration of the ketonic carbonyl group, gave the α,β-disubstitued lactone 13 . Reduction of the ketonic carbonyl of the latter using NaBH4, followed by treatment with CF3CO2H and catalytic hydrogenolysis afforded (±)-α-conidendrin 1 . DIBAL reduction of O -dibenzyl (±)-α-conidendrin 15 and subsequent methylation of the intermediate lactol and catalytic hydrogenolysis, gave methyl 1-epi-(±)-α-conidendral 3a . This compound is an epimer of methyl α-conidendral described by Cambie as having also the structure 3a . Sodium methoxide treatment of 15 followed by catalytic hydrogenolysis yielded (±)-β-conidendrin 2 . Sodium methoxide treatment of 15 followed by DIBAL reduction, subsequent methylation of the intermediate lactol and catalytic hydrogenolysis afforded methyl (±)-β-conidendral 4 , whose diacetate was identical with the compound of natural origin.

Several biaryls bearing various substituents on both rings were synthesized in a preparative fashion, and in yields up to 88% by a technical improvement on the classical Ullmann reaction. All these biaryls bear reactive functional groups (i.e. formyl, methoxycarbonyl, dimethoxycarbonylpropyl and butanolidylmethyl) in both the o and o ′ positions. The biaryls 9 , 13 , 21 and 26–33 are plausible synthons for bisbenzocyclooctadiene lignans such as schizandrin and steganacin.

Regioselective introduction of a benzoxy group, in the benzylic position of the β-benzyl-γ-butyrolactone (R)-(+)-8, was achieved by tretment with NBS followed with benzyl alcohol. α-Alkylation of the lithium enolate of the resulting intermediate 11, with O -benzylvanillyl bromide 5, gave the trans disubstituted lactone 13. Catalytic hydrogenolysis (PdC) of 13 selectively split the aryl benzyl ether linkage, thus giving the compound 14. Intramolecular Friedel-Crafts cyclisation of the latter, using the benzoxy group as the leaving group, was induced with BF3. Et2O and afforded high yields of (−)-α-conidendrin 2.

Resume The use of lithium hexamethyldisilylamide (LHDS) in α-hydroxyalkylatoin of β-(3,4-methylenedioxybenzyl)-γ-butyrolactone gives high yields of (±) podorhizol and (±) epi-podorhizol as 1:1 diastereoisomer mixture. Cyclisation of both alcohols using trifluoroacetic acid afforded only (±) isodeoxypodophyllotoxin, an “all-trans” diastereopisomer of deoxypodophyllotoxin.

Kinetically controlled intramolecular α-hydroxyalkylation of a suitable diphenyl aldehyde lactone gave a dibenzocyclooctenolactone having a cis lactone-ring junction, such as (±)-picrostegane and (±)-isopicrostegane. Subsequent transformations led to the known (±)-isostegane. The chemical properties, the physical data and biological activity of these three diastereoisomers were compared with those of(±)-stegane, a fourth diastereoisomer obtained by hydrogenolysis of synthetic (±)-steganacin.

Resume On decrit la synthese du t-propyl-6 piperidinol-3 (dl-pseudo-conhydrine) en 3 etapes a partir de reactions courantes. Ce schema reactionnel est analogue a celui propose recemment pour la biosynthese de la propyl-2 piperidine (coniine).